The prostanoid thromboxane (TX) A2 is a potent mediator of platelet aggregation and constrictor of various types of smooth muscle (SM) including vascular, renal/kidney, pulmonary/bronchial and prostate SM. TXA2 is also a potent pro-inflammatory mediator and immune modulatory agent, being abundantly produced by platelets, by various types of SM, by endothelial cells and also by inflammatory monocyte-derived macrophages. Hence, TXA2 plays an essential role in the cardiovascular (CV), renal, pulmonary and prostate systems and in immunity and inflammation. Imbalances in signalling and/or alterations in the levels of TXA2 or of its TXA2 receptor, which is also referred to as the T prostanoid receptor or, in short, as the TP, have been implicated in various cardiovascular (e.g thrombosis, atherothrombosis, peripheral arterial disease, myocardial infarction, stroke and transient ischemic attack/TIA, acute coronary syndrome/ACS, systemic and pregnancy induced hypertension), renal (including glomerular nephritis and renal hypertension), pulmonary (including asthma and pulmonary arterial hypertension/PAH) and prostate (e.g benign prostate hyperplasia/BPH) diseases, and in the several inflammatory diseases associated with those systems and conditions. More recently, the role for TXA2, TXA2 synthase (TXAS) and its receptor, the TP, in neoplastic disease has been firmly established, including in cancers of the bladder, prostate, breast and lung where TXA2 can promote tumour cell proliferation, migration, invasion, angiogenesis, inflammation and immunity, amongst other tumour-promoting actions. In humans, TXA2 actually signals through two distinct receptor (iso)forms termed TPα and TPβ that are encoded by the same gene and which differ exclusively in their intracellular carboxyl-terminal (C)-tail domains. The TPs (TPα and TPβ) are expressed in a range of cells throughout the body including in platelets, in various types of SM, in endothelial cells and in macrophages, for example.
Due to the roles of TXA2 in the CV, renal, pulmonary and prostate systems, there is significant clinical interest in the development of TP antagonists, not least for the treatment of atherothrombosis and other CV, renal and pulmonary disorders. TP antagonists also have potential applications in the treatment of various pro-inflammatory (including but not limited to inflammatory CVD, CVD associated with types 1 and 2 diabetes mellitus, renal and pulmonary diseases, post-viral/microbial infection), neoplastic and prostate (such as benign prostate hyperplasia/BPH) diseases. Other traditional therapeutic approaches currently used as alternatives to TP antagonists aim to inhibit the biosynthesis of TXA2. Amongst these are the class of cyclooxygenase (COX) inhibitors referred to as the non-steroidal anti-inflammatory drugs (NSAIDs), which includes Aspirin and related COX 1 and/or COX 2 inhibitors. These COX inhibitors act by inhibiting the conversion of arachidonic acid into the endoperoxide prostaglandin (PG) G2/PGH2, the first enzymatic step in the synthesis of TXA2 and of the related prostanoids which includes PGD2, PGE2, PGF2α and PGI2/prostacyclin. As one of the major sites of TXA2 synthesis is the anucleated platelet, which mainly express COX 1 as opposed to COX 2, low-dose Aspirin is widely used to reduce/inhibit the synthesis of TXA2 within platelets while not substantially affecting the synthesis of the other prostanoids by COX 1 or COX 2 in other nucleated cells. Hence, low-dose Aspirin is widely used to prevent excessive thrombosis in patients at risk of CV episodes by inhibiting TXA2 generation in the anucleated platelet.
Recognition for a need to develop TP antagonists has increased in recent years mainly due to the fact that such traditional approaches involving the use of low-dose Aspirin are not sufficiently efficacious, e.g., in reducing thrombosis in at-risk patients, and/or due to its associated side-effects due to its indiscriminate inhibition of the synthesis of the other prostanoids (PGD2, PGE2, PGF2α and PGI2/prostacyclin). Lack of efficacy can also occur due to the fact that a relatively high percentage of the general population displays “Aspirin-resistance”, a failure to lower TXA2 levels in response to Aspirin therapy. Furthermore, increased incidence of adverse CV episodes can occur in patients receiving COXIB (COX 2 selective inhibitors) therapy, suggesting that more targeted TP receptor antagonism, rather than COX1/2 inhibition, may be a more a clinically beneficial way to inhibit the adverse effects of TXA2. Moreover, TP antagonists, but not Aspirin or other NSAIDS or COXIBs, will inhibit the actions of TXA2 and of the free-radical derived isoprostane 8-iso-prostaglandin (PG) F2α and of all other incidental TP ligands (e.g., the endoperoxide PGG2/PGH2, 20-hydroxyeicosatetraenoic acid/20-HETE) that also act as full or partial agonists of the TP.